Abstract This application of administrative supplement is in response to NOT-AG-18-008: Alzheimer's Disease and its related Dementias (AD/ADRD)-focused Administrative supplements for NIH grants that are not focused on Alzheimer's disease. There are three main goals in our R01 project: the development of novel computational algorithms for the reconstruction of fiber orientation distribution (FOD) from multi-shell diffusion imaging data (Aim 1); the validation of FOD-based tractography on mouse imaging and tracer injection data (Aim 2); and development of tools for the computation of fiber bundles of human brains using connectome imaging data (Aim 3). In the first two years of this R01 project, we have made tremendous progresses toward these goals. We have published 8 papers in less than two years. In this administrative supplement, we propose to apply the connectome modeling tools developed in our R01 project to analyze the large-scale diffusion MRI and tau PET imaging data from ADNI3 to study the structural basis of tau pathology propagation in the development of Alzheimer?s disease (AD). While it has long been suggested in Braak stages that neuron-to-neuron propagation of tau pathology along axonal fiber tracts could play a critical role in the development of AD, the in vivo quantification of tau pathology in the brain has only been available recently with the invention of novel ligands such as AV1451 used in ADNI3. By jointly analyzing the diffusion MRI and tau PET imaging data on a large cohort of normal controls (NCs), patients with mild cognitive impairment (MCI) and AD, we aim to study the structural basis of tau pathology propagation and develop more precise imaging marker with diffusion MRI for the early diagnosis of AD. The work we propose here falls within the scope of Aim 1 and Aim 3 of the original R01 project. There are two specific aims in this administrative supplement project. 1. To study the association of fiber bundle connectivity and tau PET burden in the limbic cortical areas. 2. To study the association of tau- connectivity networks and tractography-based structural networks. With the completion of this supplemental project, we will develop a suite of tools for studying the relation of structural connectivity and tau uptake values from PET imaging. We will for the first time provide the tools to compute tau-connectivity network and examine its structural basis based on data from diffusion MRI. All the tools developed in this project will be publicly distributed to the research community on NITRC (https://www.nitrc.org).